Maternal obesity: new placental paradigms unfolded
Authors: Carolin Brombach, Wen Tong, Dino A. Giussani
Journal: Trends in Molecular Medicine (2022)

During maternal obesity, placental lipid accumulation, glycosylation end-products, and a shift in macrophage population contribute to chronic low-grade placental 'meta-inflammation'.Recent bioinformatic advances have highlighted mechanisms of placental lipid accumulation during maternal obesity, including fatty acid transporter expression, lipoprotein lipase activity, and alterations to mitochondrial metabolism.Inflammation and metabolic dysfunction increase placental oxidative and endoplasmic reticulum (ER) stress, and downstream activation of the placental unfolded protein response (UPR), all of which have been linked to complications of pregnancy, including fetal growth restriction, preeclampsia, and gestational diabetes.Human umbilical vein endothelial cells isolated from mothers with a high body mass index show evidence of ER stress, which can be recapitulated using high levels of glucose, palmitate, or acidosis in the culture medium.Recent evidence suggests that ER stress and UPR activation mediate adverse placental effects through alterations of nitric oxide metabolism and a shift in angiogenic balance. The prevalence of maternal obesity is increasing at an alarming rate, and is providing a major challenge for obstetric practice. Adverse effects on maternal and fetal health are mediated by complex interactions between metabolic, inflammatory, and oxidative stress signaling in the placenta. Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are common downstream pathways of cell stress, and there is evidence that this conserved homeostatic response may be a key mediator in the pathogenesis of placental dysfunction. We summarize the current literature on the placental cellular and molecular changes that occur in obese women. A special focus is cast onto placental ER stress in obese pregnancy, which may provide a novel link for future investigation. The prevalence of maternal obesity is increasing at an alarming rate, and is providing a major challenge for obstetric practice. Adverse effects on maternal and fetal health are mediated by complex interactions between metabolic, inflammatory, and oxidative stress signaling in the placenta. Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are common downstream pathways of cell stress, and there is evidence that this conserved homeostatic response may be a key mediator in the pathogenesis of placental dysfunction. We summarize the current literature on the placental cellular and molecular changes that occur in obese women. A special focus is cast onto placental ER stress in obese pregnancy, which may provide a novel link for future investigation. The rising incidence of obesity worldwide is becoming an increasing challenge for modern society because it is a major detriment to human health and a cause of morbidity across generations [1.Crujeiras A.B. Casanueva F.F. Obesity and the reproductive system disorders: epigenetics as a potential bridge.Hum. Reprod. 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The placenta, sitting at the interface between mother and fetus and mediating nutrient and gaseous exchange, is a key determinant of pregnancy success. In contrast to the wealth of research on offspring and maternal outcomes, investigation of the placenta in obese pregnancy has been comparatively limited. To date, such work has focused on the relationship between maternal obesity during pregnancy and metabolism, inflammation, and oxidative stress (see Glossary) in the placenta. A separate but related cell-stress mechanism is ER stress and its subsequent UPR. Despite mounting evidence that these adaptive pathways can trigger adverse consequences for maternal and fetal health [10.Mizuuchi M. et al.Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor via ATF4 and ATF6β: implications for the pathophysiology of human pregnancy complications.J. 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Placental metabolism: substrate requirements and the response to stress.Reprod. Domest. Anim. 2016; 51: 25-35Crossref PubMed Scopus (30) Google Scholar]. In an obesogenic environment, nutrient excess drives anabolism and storage of lipids. These metabolic repercussions not only affect adipocytes but also a wide range of tissues and organs including skeletal muscle, the liver, pancreas, and brain [14.Kim J.B. Dynamic cross talk between metabolic organs in obesity and metabolic diseases.Exp. Mol. Med. 2016; 48e214Crossref Scopus (17) Google Scholar]. Obesity during pregnancy also contributes to metabolic dysregulation in the placenta. Recent bioinformatic techniques such as genome-wide transcriptome analysis, proteomics, and epigenetics have shed light onto the effects of maternal obesity on placental lipid metabolism [15.Li J.W. et al.The effects of maternal obesity on porcine placental efficiency and proteome.Animals. 2019; 9: 546Crossref Scopus (4) Google Scholar, 16.Narapareddy L. et al.Maternal weight affects placental DNA methylation of genes involved in metabolic pathways in the common marmoset monkey (Callithrix jacchus).Am. J. Primatol. 2020; 82e23101Crossref PubMed Scopus (4) Google Scholar, 17.Shrestha D. et al.Maternal dyslipidemia during early pregnancy and epigenetic ageing of the placenta.Epigenetics. 2019; 14: 1030-1039Crossref PubMed Scopus (12) Google Scholar, 18.Saben J. et al.Maternal obesity is associated with a lipotoxic placental environment.Placenta. 2014; 35: 171-177Crossref PubMed Scopus (186) Google Scholar]. Investigations show altered lipid transport mechanisms into and out of the obese placenta, such as changes in the expression of the fatty acid transporters fatty acid transport protein 2 (FATP2) and FATP4, with adverse consequences for placental function and maternal and fetal metabolism [19.Zhu M.J. et al.Maternal obesity markedly increases placental fatty acid transporter expression and fetal blood triglycerides at midgestation in the ewe.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010; 299: R1224-R1231Crossref PubMed Scopus (103) Google Scholar, 20.Lager S. et al.Protein expression of fatty acid transporter 2 is polarized to the trophoblast basal plasma membrane and increased in placentas from overweight/obese women.Placenta. 2016; 40: 60-66Crossref PubMed Google Scholar, 21.Qiao L. et al.Maternal high-fat feeding increases placental lipoprotein lipase activity by reducing SIRT1 expression in mice.Diabetes. 2015; 64: 3111-3120Crossref PubMed Scopus (21) Google Scholar, 22.Louwagie E.J. et al.Placental lipid processing in response to a maternal high-fat diet and diabetes in rats.Pediatr. Res. 2018; 83: 712-722Crossref PubMed Scopus (19) Google Scholar, 23.Tian L. et al.The effect of maternal obesity on fatty acid transporter expression and lipid metabolism in the full-term placenta of lean breed swine.J. Anim. Physiol. Anim. Nutr. 2018; 102: e242-e253Crossref PubMed Scopus (0) Google Scholar, 24.Segura M.T. et al.Maternal BMI and gestational diabetes alter placental lipid transporters and fatty acid composition.Placenta. 2017; 57: 144-151Crossref PubMed Scopus (58) Google Scholar, 25.Dubé E. et al.Modulation of fatty acid transport and metabolism by maternal obesity in the human full-term placenta.Biol. Reprod. 2012; 87: 1-11Crossref Scopus (0) Google Scholar]. This is associated with significant changes to the lipid profile of obese placentae . Other studies have reported that placentae from obese compared to lean mothers show high total lipid content and increased levels of triglycerides (TGs), free fatty acids (FFAs), non-esterified fatty acids (NEFAs), and cholesterol, not only in human subjects but also in experimental animal models, including the pregnant mouse, rat, ewe, and sow (Table 1). These findings may at least in part be attributed to increased lipoprotein lipase activity in obese placentae of these species [21.Qiao L. et al.Maternal high-fat feeding increases placental lipoprotein lipase activity by reducing SIRT1 expression in mice.Diabetes. 2015; 64: 3111-3120Crossref PubMed Scopus (21) Google Scholar,23.Tian L. et al.The effect of maternal obesity on fatty acid transporter expression and lipid metabolism in the full-term placenta of lean breed swine.J. Anim. Physiol. Anim. Nutr. 2018; 102: e242-e253Crossref PubMed Scopus (0) Google Scholar,25.Dubé E. et al.Modulation of fatty acid transport and metabolism by maternal obesity in the human full-term placenta.Biol. Reprod. 2012; 87: 1-11Crossref Scopus (0) Google Scholar]. In addition, placentae from obese women show a reduced mitochondrial content and lower expression of acylcarnintine, suggesting reduced capacity for β-oxidation [26.Calabuig-Navarro V. et al.Effect of maternal obesity on placental lipid metabolism.Endocrinology. 2017; 158: 2543-2555Crossref PubMed Scopus (74) Google Scholar]. This placental phenotype favors lipid accumulation, reduces lipid transport to the developing fetus. and thereby limits excess fetal adiposity. The trade-off may be a lipotoxic environment within the placenta that predisposes to cell stress and inflammation. It is also known that subtypes of fatty acids vary in functional significance, and inconsistencies have been reported about polyunsaturated fatty acids (PUFAs) in the obese placenta. PUFAs include essential fatty acids, such as the ω3 and ω6 fatty acids, which are required for cell growth and inflammatory pathways [27.Glick N. Fischer M. The role of essential fatty acids in human health.J. Evid. Based Complement. Altern. Med. 2013; 18: 268-289Crossref Scopus (0) Google Scholar]. Optimal PUFA status is essential for fetal and placental development, and changes in either direction can have unfavorable consequences on pregnancy outcome [28.Hirschmugl B. et al.Maternal obesity modulates intracellular lipid turnover in the human term placenta.Int. J. Obes. 2017; 41: 317-323Crossref PubMed Scopus (0) Google Scholar, 29.Brenna J.T. Animal studies of the functional consequences of suboptimal polyunsaturated fatty acid status during pregnancy, lactation and early post-natal life.Matern. Child Nutr. 2011; 7: 59-79Crossref PubMed Scopus (0) Google Scholar, 30.Gázquez A. et al.Altered materno-fetal transfer of 13C-polyunsaturated fatty acids in obese pregnant women.Clin. Nutr. 2020; 39: 1101-1107Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Higher placental PUFA levels have been reported in obese compared to lean women [24.Segura M.T. et al.Maternal BMI and gestational diabetes alter placental lipid transporters and fatty acid composition.Placenta. 2017; 57: 144-151Crossref PubMed Scopus (58) Google Scholar,31.Furse S. et al.A high-throughput platform for detailed lipidomic analysis of a range of mouse and human tissues.Anal. Bioanal. Chem. 2020; 412: 2851-2862Crossref PubMed Scopus (13) Google Scholar], although a separate study showed effects in the opposite direction [32.Fattuoni C. et al.Preliminary metabolomics analysis of placenta in maternal obesity.Placenta. 2018; 61: 89-95Crossref PubMed Scopus (39) Google Scholar]. The nature of these discrepancies remains to be resolved, but some studies suggest that PUFA levels in humans may be influenced by fetal sex and maternal diet [33.Alvarado F.L. et al.Maternal obesity is not associated with placental lipid accumulation in women with high omega-3 fatty acid levels.Placenta. 2018; 69: 96-101Crossref PubMed Scopus (11) Google Scholar,34.Powell T.L. et al.Sex-specific responses in placental fatty acid oxidation, esterification and transfer capacity to maternal obesity.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2021; 1866158861PubMed Google Scholar].Table 1Changes to lipid and glucose metabolism in the placentae of obese pregnanciesaKey: ↑, increased compared to lean pregnancies; ↓, decreased compared to lean pregnancies; ↔, no difference between obese versus lean pregnancies.MarkerRegulationModel organismRefsLipid metabolismTotal lipid content↑HumanMouseRatSow[13.Vaughan O. Fowden A. Placental metabolism: substrate requirements and the response to stress.Reprod. Domest. Anim. 2016; 51: 25-35Crossref PubMed Scopus (30) Google Scholar,26.Calabuig-Navarro V. et al.Effect of maternal obesity on placental lipid metabolism.Endocrinology. 2017; 158: 2543-2555Crossref PubMed Scopus (74) Google Scholar,129.Martino J. et al.Maternal body weight and gestational diabetes differentially influence placental and pregnancy outcomes.J. Clin. Endocrinol. Metab. 2016; 101: 59-68Crossref PubMed Scopus (76) Google Scholar][130.Fernandez-Twinn D.S. et al.Exercise rescues obese mothers' insulin sensitivity, placental hypoxia and male offspring insulin sensitivity.Sci. Rep. 2017; 7: 44650Crossref PubMed Scopus (0) Google Scholar][22.Louwagie E.J. et al.Placental lipid processing in response to a maternal high-fat diet and diabetes in rats.Pediatr. Res. 2018; 83: 712-722Crossref PubMed Scopus (19) Google Scholar][23.Tian L. et al.The effect of maternal obesity on fatty acid transporter expression and lipid metabolism in the full-term placenta of lean breed swine.J. Anim. Physiol. Anim. Nutr. 2018; 102: e242-e253Crossref PubMed Scopus (0) Google Scholar]TG↑HumanMouseRatSow[26.Calabuig-Navarro V. et al.Effect of maternal obesity on placental lipid metabolism.Endocrinology. 2017; 158: 2543-2555Crossref PubMed Scopus (74) Google Scholar,28.Hirschmugl B. et al.Maternal obesity modulates intracellular lipid turnover in the human term placenta.Int. J. Obes. 2017; 41: 317-323Crossref PubMed Scopus (0) Google Scholar,131.Malti N. et al.Oxidative stress and maternal obesity: feto-placental unit interaction.Placenta. 2014; 35: 411-416Crossref PubMed Scopus (56) Google Scholar][21.Qiao L. et al.Maternal high-fat feeding increases placental lipoprotein lipase activity by reducing SIRT1 expression in mice.Diabetes. 2015; 64: 3111-3120Crossref PubMed Scopus (21) Google Scholar][22.Louwagie E.J. et al.Placental lipid processing in response to a maternal high-fat diet and diabetes in rats.Pediatr. Res. 2018; 83: 712-722Crossref PubMed Scopus (19) Google Scholar][23.Tian L. et al.The effect of maternal obesity on fatty acid transporter expression and lipid metabolism in the full-term placenta of lean breed swine.J. Anim. Physiol. Anim. Nutr. 2018; 102: e242-e253Crossref PubMed Scopus (0) Google Scholar,75.Liang T. et al.Maternal obesity stimulates lipotoxicity and up-regulates inflammatory signaling pathways in the full-term swine placenta.Anim. Sci. J. 2018; 89: 1310-1322Crossref PubMed Scopus (9) Google Scholar,105.Hu C. et al.Maternal diet-induced obesity compromises oxidative stress status and angiogenesis in the porcine placenta by upregulating Nox2 expression.Oxidative Med. Cell. Longev. 2019; 20192481592Crossref Scopus (21) Google Scholar]FFA↔↑HumanEweSow[26.Calabuig-Navarro V. et al.Effect of maternal obesity on placental lipid metabolism.Endocrinology. 2017; 158: 2543-2555Crossref PubMed Scopus (74) Google Scholar][19.Zhu M.J. et al.Maternal obesity markedly increases placental fatty acid transporter expression and fetal blood triglycerides at midgestation in the ewe.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010; 299: R1224-R1231Crossref PubMed Scopus (103) Google Scholar][23.Tian L. et al.The effect of maternal obesity on fatty acid transporter expression and lipid metabolism in the full-term placenta of lean breed swine.J. Anim. Physiol. Anim. Nutr. 2018; 102: e242-e253Crossref PubMed Scopus (0) Google Scholar,75.Liang T. et al.Maternal obesity stimulates lipotoxicity and up-regulates inflammatory signaling pathways in the full-term swine placenta.Anim. Sci. J. 2018; 89: 1310-1322Crossref PubMed Scopus (9) Google Scholar,105.Hu C. et al.Maternal diet-induced obesity compromises oxidative stress status and angiogenesis in the porcine placenta by upregulating Nox2 expression.Oxidative Med. Cell. Longev. 2019; 20192481592Crossref Scopus (21) Google Scholar]Cholesterol↑HumanSow[26.Calabuig-Navarro V. et al.Effect of maternal obesity on placental lipid metabolism.Endocrinology. 2017; 158: 2543-2555Crossref PubMed Scopus (74) Google Scholar][23.Tian L. et al.The effect of maternal obesity on fatty acid transporter expression and lipid metabolism in the full-term placenta of lean breed swine.J. Anim. Physiol. Anim. Nutr. 2018; 102: e242-e253Crossref PubMed Scopus (0) Google Scholar]NEFAs↑RatSow[22.Louwagie E.J. et al.Placental lipid processing in response to a maternal high-fat diet and diabetes in rats.Pediatr. Res. 2018; 83: 712-722Crossref PubMed Scopus (19) Google Scholar][75.Liang T. et al.Maternal obesity stimulates lipotoxicity and up-regulates inflammatory signaling pathways in the full-term swine placenta.Anim. Sci. J. 2018; 89: 1310-1322Crossref PubMed Scopus (9) Google Scholar,105.Hu C. et al.Maternal diet-induced obesity compromises oxidative stress status and angiogenesis in the porcine placenta by upregulating Nox2 expression.Oxidative Med. Cell. Longev. 2019; 20192481592Crossref Scopus (21) Google Scholar]PUFAs↓↑HumanHuman[34.Powell T.L. et al.Sex-specific responses in placental fatty acid oxidation, esterification and transfer capacity to maternal obesity.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2021; 1866158861PubMed Google Scholar] (male fetus), [32.Fattuoni C. et al.Preliminary metabolomics analysis of placenta in maternal obesity.Placenta. 2018; 61: 89-95Crossref PubMed Scopus (39) Google Scholar,33.Alvarado F.L. et al.Maternal obesity is not associated with placental lipid accumulation in women with high omega-3 fatty acid levels.Placenta. 2018; 69: 96-101Crossref PubMed Scopus (11) Google Scholar] (Western diet) [24.Segura M.T. et al.Maternal BMI and gestational diabetes alter placental lipid transporters and fatty acid composition.Placenta. 2017; 57: 144-151Crossref PubMed Scopus (58) Google Scholar,31.Furse S. et al.A high-throughput platform for detailed lipidomic analysis of a range of mouse and human tissues.Anal. Bioanal. Chem. 2020; 412: 2851-2862Crossref PubMed Scopus (13) Google Scholar]Glucose metabolismGLUT1↑↓HumanMouseRatRat[132.James-Allan L.B. et al.Insulin stimulates GLUT4 trafficking to the syncytiotrophoblast basal plasma membrane in the human placenta.J. Clin. Endocrinol. Metab. 2019; 104: 4225-4238Crossref Scopus (5) Google Scholar][133.Jones H.N. et al.High-fat diet before and during pregnancy causes marked up-regulation of placental nutrient transport and fetal overgrowth in C57/BL6 mice.FASEB J. 2009; 23: 271-278Crossref PubMed Scopus (154) Google Scholar][134.Reynolds C.M. et al.Maternal high fat and/or salt consumption induces sex-specific inflammatory and nutrient transport in the rat placenta.Physiol. Rep. 2015; 3e12399Crossref Scopus (48) Google Scholar] (male fetus), [135.Lin Y. et al.Beneficial effects of dietary fibre supplementation of a high-fat diet on fetal development in rats.Br. J. Nutr. 2011; 106: 510-518Crossref PubMed Scopus (0) Google Scholar][136.Lineker C. et al.High fructose consumption in pregnancy alters the perinatal environment without increasing metabolic disease in the offspring.Reprod. Fertil. Dev. 2016; 28: 2007-2015Crossref PubMed Scopus (12) Google Scholar]GLUT3↑↓MouseRatRat[137.Sferruzzi-Perri A.N. et al.An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory.FASEB J. 2013; 27: 3928-3937Crossref PubMed Scopus (0) Google Scholar][135.Lin Y. et al.Beneficial effects of dietary fibre supplementation of a high-fat diet on fetal development in rats.Br. J. Nutr. 2011; 106: 510-518Crossref PubMed Scopus (0) Google Scholar][22.Louwagie E.J. et al.Placental lipid processing in response to a maternal high-fat diet and diabetes in rats.Pediatr. Res. 2018; 83: 712-722Crossref PubMed Scopus (19) Google Scholar]GLUT4↑↓RatHuman[134.Reynolds C.M. et al.Maternal high fat and/or salt consumption induces sex-specific inflammatory and nutrient transport in the rat placenta.Physiol. Rep. 2015; 3e12399Crossref Scopus (48) Google Scholar] (male fetus)[132.James-Allan L.B. et al.Insulin stimulates GLUT4 trafficking to the syncytiotrophoblast basal plasma membrane in the human placenta.J. Clin. Endocrinol. Metab. 2019; 104: 4225-4238Crossref Scopus (5) Google Scholar,138.Colomiere M. et al.Defective insulin signaling in placenta from pregnancies complicated by gestational diabetes mellitus.Eur. J. Endocrinol. 2009; 160: 567-578Crossref PubMed Scopus (137) Google Scholar]AGEs↑Human[20.Lager S. et al.Protein expression of fatty acid transporter 2 is polarized to the trophoblast basal plasma membrane and increased in placentas from overweight/obese women.Placenta. 2016; 40: 60-66Crossref PubMed Google Scholar,40.Antoniotti G.S. et al.Obesity associated advanced glycation end products within the human uterine cavity adversely impact endometrial function and embryo implantation competence.Hum. Reprod. 2018; 33: 654-665Crossref PubMed Scopus (19) Google Scholar]Glycogen deposition↑Mouse[43.Nam J. et al.Choline prevents fetal overgrowth and normalizes placental fatty acid and glucose metabolism in a mouse model of maternal obesity.J. Nutr. Biochem. 2017; 49: 80-88Crossref PubMed Scopus (0) Google Scholar]a Key: ↑, increased compared to lean pregnancies; ↓, decreased compared to lean pregnancies; ↔, no difference between obese versus lean pregnancies. Open table in a new tab Glucose is the main source of energy for both the placenta and the developing fetus in humans [35.Hauguel S. et al.Metabolism of the human placenta perfused in vitro: glucose transfer and utilization, O2 consumption, lactate and ammonia production.Pediatr. Res. 1983; 17: 729-732Crossref PubMed Google Scholar]. Because the fetus has a limited capacity for gluconeogenesis, it is almost entirely dependent on glucose transfer from the mother, as determined by placental glucose metabolism and transporter density [36.Joshi N.P. et al.Role of placental glucose transporters in determining fetal growth.Reprod. Sci. 2021; (Published online August 2, 2021)https://doi.org/10.1007/s43032-021-00699-9Crossref PubMed Scopus (3) Google Scholar]. Placental glucose metabolism not only involves anabolic processes, including glycogen and lipid synthesis from glucose, but also catabolic processes, including glycolysis to produce lactate and oxidative phosphorylation [35.Hauguel S. et al.Metabolism of the human placenta perfused in vitro: glucose transfer and utilization, O2 consumption, lactate and ammonia production.Pediatr. Res. 1983; 17: 729-732Crossref PubMed Google Scholar,37.Bax B.E. Bloxam D.L. Energy metabolism and glycolysis in human placental trophoblast cells during differentiation.Biochim. Biophys. Acta. 1997; 1319: 283-292Crossref PubMed Scopus (57) Google Scholar]. Glucose transfer to the fetus occurs via facilitated transport down its concentration gradient, mainly mediated by the glucose transporter (GLUT) family. The expression of different isoforms of the GLUT transporter is altered by an obesogenic maternal environment, and these alterations seem to mirror the trends in fetal growth and birth weight at term (Table 1) [38.Fowden A.L. et al.Effects of maternal obesity on placental phenotype.Curr. Vasc. Pharmacol. 2021; 19: 113-131Crossref PubMed Scopus (8) Google Scholar,39.Sferruzzi-Perri A.N. Camm E.J. The programming power of the placenta.Front. Physiol. 2016; 7: 33Crossref PubMed Scopus (112) Google Scholar]. In most cases, high-fat and high-sugar diets lead to increased expression of GLUT1 and GLUT3 that is associated with increased materno-fetal clearance of glucose. However, inconsistencies have been reported which may be related to differences in species, diet composition, and/or the timing of onset of the obesogenic diet (Table 1). In humans, increased glucose bioavailability in the uteroplacental circulation predisposes to the glycosylation of proteins and lipids, and these advanced glycosylation end-products (AGEs) have been shown to accumulate in obese placentae [20.Lager S. et al.Protein expression of fatty acid transporter 2 is polarized to the trophoblast basal plasma membrane and increased in placentas from overweight/obese women.Placenta. 2016; 40: 60-66Crossref PubMed Google Scholar,40.Antoniotti G.S. et al.Obesity associated advanced glycation end products within the human uterine cavity adversely impact endometrial function and embryo implantation competence.Hum. Reprod. 2018; 33: 654-665Crossref PubMed Scopus (19) Google Scholar]. AGEs are powerful inducers of inflammatory and cell stress pathways [20.Lager S. et al.Protein expression of fatty acid transporter 2 is polarized to the trophoblast basal plasma membrane and increased in placentas from overweight/obese women.Placenta. 2016; 40: 60-66Crossref PubMed Google Scholar,40.Antoniotti G.S. et al.Obesity associated advanced glycation end products within the human uterine cavity adversely impact endometrial function and embryo implantation competence.Hum. Reprod. 2018; 33: 654-665Crossref PubMed Scopus (19) Google Scholar]. Increased glucose availability may also affect placental glycogen storage. In healthy pregnancy, placental glycogen storage begins early in the first trimester and is proposed to function as a glucose reservoir to meet fetoplacental energy demands in late gestation [41.Akison L.K. et al.Review: alterations in placental glycogen deposition in complicated pregnancies: Current preclinical and clinical evidence.Placenta. 2017; 54: 52-58Crossref PubMed Scopus (35) Google Scholar]. Alterations in placental glycogen deposition have been described in pre-eclampsia, fetal growth restriction [41.Akison L.K. et al.Review: alterations in placental glycogen deposition in complicated pregnancies: Current preclinical and clinical evidence.Placenta. 2017; 54: 52-58Crossref PubMed Scopus (35) Google Scholar,42.Arkwright P.D. et al.Pre-eclampsia is associated with an increase in trophoblast glycogen content and glycogen synthase activity, similar to that found in hydatidiform moles.J. Clin. Invest. 1993; 91: 2744-2753Crossref PubMed Google Scholar], and gestational diabetes or obesity [41.Akison L.K. et al.Review: alterations in placental glycogen deposition in compli